Therapeutic compounds

ABSTRACT

The invention provides compounds of formula I, II, and III as defined herein, as well as salts thereof. The compounds may have activity as anti-proliferative agents.

PRIORITY OF INVENTION

This application claims priority from U.S. Provisional Application No.60/953,648, filed 2 Aug. 2007, which application is incorporated byreference.

BACKGROUND OF THE INVENTION

A diverse array of compounds, including anthraquinones, acridines,cationic porphyrins, perylenes, thidium derivatives, fluorenones,pentacyclic acridinium salts, fluoroquinophenoxazines, and otherspecific miscellaneous polycyclic compounds, have been reported tostabilize G-quadruplex DNA. Most of these compounds have little or noselectivity for G-quadruplex vs. duplex DNA.

Telomestatin is a natural product isolated from Streptomyces anulatus3533-SV4 (Shin-ya et al., J. Am. Chem. Soc., 2001, 123, 1262-1263). Atthe time of its discovery, telomestatin was viewed as the most potentinhibitor of telomerase. In vitro, telomestatin stabilizes G-quadruplexvs. duplex DNA in a 70:1 ratio (Kim et al., Cancer Res., 2003, 63,3247-3256). It has been suggested that telomestatin also inhibitstelomerase function in vivo, since cells treated with the naturalproduct exhibit a cellular senescence phenotype. Like telomeredysfunction, telomestatin activates the ATM signaling pathway. While theprecise mechanism by which telomestatin interacts with a G-quadruplexhas not been definitively elucidated, telomestatin does suppress theplating efficiency of K62 leukemia cells but has a much lesser effect onburst-forming units—erythrocyte (BFU-E) and colony-formingunits—granulocyte/macrophage (CFU-GM) from natural bone marrowCD34-positive cells (Tauchi et al., Oncogene, 2003, 22, 5338-5347).

The anticancer potential of telomestatin resides in its telomeraseinhibitory activity (IC₅₀ 5 nM) and in its ability to enhance apoptosis.Telomestatin has been evaluated for cytotoxicity in the humanneuroblastoma cell lines SK-N-AS, LANS, WAC2, and LAN1 with IC₅₀ valuesof 0.8, 2.5, 3.2, and 4.0 μM respectively (Binz et al., Eur. J. Cancer,2005, 41, 2873-2881) and in the human pancreatic carcinoma MiaPaCa withan IC₅₀ value of 0.5 μM (Liu et al., Nucleosides, Nucleotides, andNucleic Acids, 2005, 24, 1801-1815).

Another macrocyclic polyoxazole, YM-216391 isolated from Streptomycesnobilis is active against the human breast cancer cell lines HBC-4,BSY-1, HBC-5, MCF-7, and MDA-MB-231 with GI₅₀ values ranging from 15-33nM (Sohda, K-y., et al., J. Antibiotics, 2005, 58, 27-31 and Sohda,K-y., et al., Hiramoto, M., Suzumura, K-i., Takebayashi, Y., Suzuki,K-i., Tanaka, A. J. Antibiotics, 2005, 58, 32-36).

The mechanism of action of YM-216391 has not yet been elucidated.

Currently, there is a need for novel therapeutic agents and therapeuticmethods that are useful for treating diseases such as cancer. Suchagents may have improved binding affinity for G-quadruplex DNA and/orthey may have advantageous drug-like properties.

SUMMARY OF THE INVENTION

The present invention provides compounds that exhibit anti-cancerproperties. Accordingly, in one embodiment of the invention there isprovided a compound of the invention which is compound of formula (I):

wherein:

the bond represented by

is a single or double bond;

A is (—C(═O)NH—CH(R)—)_(x) or (—CH(R)—NH—C(═O)—)_(x);

B is a group of formula:

C is (—C(═O)NH—CH(R)—)_(y or) (—CH(R)—NH—C(═O)—)_(y);

n is 0, 1 or 2;

p is 0, 1, or 2;

x is 1 or 2;

y is 0, 1 or 2;

provided that the sum of n, p, x and y is 4;

X is O, S or NH;

one of W and Z is O, S or NH and the other of W and Z is CR⁶;

each of R¹, R², R³, R⁴, R⁵ and R⁶ is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl or heteroaryl, wherein each(C₁-C₆)alkyl and (C₁-C₆)alkoxy is optionally substituted with OH,(C₁-C₆)alkoxy, (C₁-C₆)allylthio, aryl, NR⁷R⁸, or —C(═O)NR⁹R¹⁰; andwherein each aryl or heteroaryl is optionally substituted with one ortwo substituents selected independently from a halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR⁷R⁸, and NR⁷R⁸(C₁-C₆)alkyl-;

each R is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkoxy, aryl or heteroaryl, wherein each (C₁-C₆)alkyl,(C₂-C₆)alkenyl and (C₁-C₆)alkoxy is optionally substituted with OH,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR¹¹R¹², or —C(═O)NR¹³R¹⁴; andwherein each aryl or heteroaryl is optionally substituted with one ortwo substituents selected independently from halo, (C₁-C₆)alkyl,NR¹¹R¹², and NR¹³R¹⁴(C₁-C₆)alkyl-;

each of R⁷ and R⁸ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, arylcarbonyl, heteroarylcarbonyl,(C₁-C₆)alkoxycarbonyl, carbamoyl, N—(C₁-C₆)alkylaminocarbonyl, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or(C₁-C₆)alkoxycarbony is optionally substituted with one or more NR¹⁵R¹⁶;or R⁷ and R⁸ together with the nitrogen to which they are attached forma pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, orazepino ring; and

each of R⁹ and R¹⁰ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R⁹ and R¹⁰ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring;

each of R¹¹ and R¹² is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹¹ and R¹² together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and

each of R¹³ and R¹⁴ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring;

each of R¹⁵ and R¹⁶ is independently hydrogen, (C₁-C₆)alkyl, or(C₁-C₆)alkanoyl; or R¹⁵ and R¹⁶ together with the nitrogen to which theyare attached form a pyrrolidino, piperidino, piperazino, morpholino,thiomorpholino, or azepino ring;

or a salt thereof.

In one embodiment of the invention the compound of formula (I) is notYM-216391.

In one embodiment the invention also provides a compound of formula (II)or (III):

wherein:

each X is independently O, S or NH;

each R is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkoxy, aryl or heteroaryl, wherein each (C₁-C₆)alkyl,(C₂-C₆)alkenyl or (C₁-C₆)alkoxy is optionally substituted with OH,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR¹¹R¹²; or —C(═O)NR¹³R¹⁴; andwherein each aryl or heteroaryl is optionally substituted with one ortwo substituents selected independently from halo, (C₁-C₆)alkyl,NR¹¹R¹²; and NR¹³R¹⁴(C₁-C₆)alkyl-;

each of R¹¹ and R¹² is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹¹ and R¹² together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and

each of R¹³ and R¹⁴ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring;

each of R¹⁵ and R¹⁶ is independently hydrogen, (C₁-C₆)alkyl or(C₁-C₆)alkanoyl; or R¹⁵ and R¹⁶ together with the nitrogen to which theyare attached form a pyrrolidino, piperidino, piperazino, morpholino,thiomorpholino, or azepino ring;

or a salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), (II), or (III) or a pharmaceutically acceptablesalt thereof, in combination with a pharmaceutically acceptable diluentor carrier.

Additionally, the invention provides a therapeutic method for treatingcancer comprising administering to a mammal (e.g., a human male orfemale) in need of such therapy, an effective amount of a compound offormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof.

The invention also provides a compound of formula (I), (II), or (III) ora pharmaceutically acceptable salt thereof for use in medical therapy(e.g., for use in treating cancer), as well as the use of a compound offormula (I), (II), or (III) or a pharmaceutically acceptable saltthereof for the manufacture of a medicament useful for the treatment ofcancer in a mammal, such as a human.

The invention also provides a compound of formula (I), (II), or (III),or a pharmaceutically acceptable salt thereof for use in theprophylactic or therapeutic treatment of cancer.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula (I), (H), or (III) orsalts thereof.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straightand branched groups; but reference to an individual radical such aspropyl embraces only the straight chain radical, a branched chain isomersuch as isopropyl being specifically referred to. Aryl denotes a phenylradical or an ortho-fused bicyclic carbocyclic radical having about nineto ten ring atoms in which at least one ring is aromatic. Heteroaryldenotes an aromatic heterocyclic ring containing 5 or 6-ring membersincluding from one to four ring hetero atoms selected from oxygen,sulfur and nitrogen, the remainder being carbon, which ring isoptionally ortho-fused to a benzene ring or another 5- or 6-memberedheteroaromatic ring.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C₂-C₆)alkenylcan be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C₁-C₆)alkanoyl can beacetyl, propanoyl or butanoyl; (C₁-C₆)alkoxy can be methoxy, ethoxy,propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy,or hexyloxy; and aryl can be phenyl, indenyl, or naphthyl. Aryl can bephenyl. Heteroaryl can be pyridyl.

An example of the bond represented by

is a double bond.

In one embodiment, the compound of formula (I) is a compound of formula(I′)

An example of a particular value for each X in the compounds of formulae(I) and (I′) is O.

Examples for each group of formula —C(═O)NH—CH(R)— are residues of D- orL-amino acids, such as D- or L-glycine, alanine, valine, leucine,isoleucine and phenylalanine, more particularly alanine, valine,leucine, isoleucine, and phenylalanine.

Examples of particular values for R are independently hydrogen, methyl,isopropyl, 1-methylpropyl, 2-methylpropyl and benzyl, more particularlymethyl, isopropyl, 1-methylpropyl, 2-methylpropyl and benzyl.

Examples of particular values for R are independently (C₁-C₆)alkyl or(C₂-C₆)alkenyl wherein each (C₁-C₆)alkyl, and (C₂-C₆)alkenyl, isoptionally substituted with NR¹¹R¹².

Examples of particular values for R are independently aminomethyl,2-aminoethyl, 3-aminopropyl or 4-aminobutyl.

A particular value for R¹ is hydrogen.

A particular value for R² is hydrogen.

A particular value for R³ is hydrogen or —(CH₂)_(q)—NR^(a)R^(b) in whichq is 1, 2, 3 or 4, R^(a) is hydrogen and R^(b) is acetyl, benzoyl,pyridylcarbonyl, methoxycarbonyl, N-methylaminocarbonyl or phenyl.

A particular value for R⁴ is hydrogen.

A particular value for R⁵ is hydrogen; methyl, phenyl,N-methylaminophenyl, N-acetylaminoethylphenyl, pyridyl, ormethoxypyridyl.

A particular value for R⁶ is hydrogen.

A particular value for A is —C(═O)NH—CH(R)—.

A particular value for A is —C(═O)NH—CH(R)—C(═O)NH—CH(R)—.

A particular value for A is —C(═O)NH—CH₂—.

A particular value for A is —C(═O)NH—CH₂—C(═O)NH—CH₂—.

A particular value for A is —CH(R)—NH—C(═O)—.

A particular value for A is —CH(R)—NH—C(═O)—CH(R)—NH—C(═O)—.

A particular value for A is —CH₂—NH—C(═O)—.

A particular value for A is —CH₂NH—C(═O)—CH₂—NH—C(═O)—.

A specific compound of formula (I) is:

A specific compound of formula (I) is:

A specific compound of formula (I) is:

A specific compound of formula (I) is:

A specific compound of formula (I) is:

A specific compound of formula (I) is:

A specific group of compounds are compounds wherein W is O or S and Z isCR⁶.

A specific group of compounds are compounds wherein Z is O or S and W isCR⁶.

In one embodiment of the invention the compound of formula (I) is not acompound of the following formula:

In one embodiment of the invention the compound of formula (I) is not acompound of the following formula:

Representative examples of compounds of formula (I) are compounds offormula:

In one embodiment the invention provides a compound of formula (I)wherein x is 1, y is 0 and n+p is 1, 2 or 4 and wherein x is 1, y is 1,p is 1 and n is 0 or 2.

In one embodiment the invention provides a compound of formula (I)wherein x is 1, y is 0 and n+p is 1, 2 or 4.

In one embodiment the invention provides a compound of formula (I)wherein x is 1, y is 1, p is 1 and n is 0 or 2.

In one embodiment of the invention there is provided a compound of theinvention which is compound of formula (I):

wherein:

the bond represented by

is a single or double bond;

A is (—C(═O)NH—CH(R)—)_(x) or (—CH(R)—NH—C(═O)—)_(x);

B is a group of formula:

C is (—C(═O)NH—CH(R)—)_(y or) (—CH(R)—NH—C(═O)—)_(y);

n is 0, 1 or 2;

p is 0, 1, or 2;

x is 1 or 2;

y is 0, 1 or 2;

provided that the sum of n, p, x and y is 4;

X is O, S or NH;

one of W and Z is O, S or NH and the other of W and Z is CR⁶;

each of R¹, R², R³, R⁴, R⁵ and R⁶ is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl, or heteroaryl, wherein each(C₁-C₆)alkyl and (C₃-C₆)alkoxy is optionally substituted with OH,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR⁷R⁸, or —C(═O)NR⁹R¹⁰; andwherein each aryl or heteroaryl is optionally substituted with one ortwo substituents selected independently from a halo, (C₁-C₆)alkyl,NR⁷R⁸, and NR⁷R⁸(C₁-C₆)alkyl-;

each R is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl, orheteroaryl, wherein each (C₁-C₆)alkyl and (C₁-C₆)alkoxy is optionallysubstituted with OH, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR¹¹R¹², or—C(═O)NR¹³R¹⁴; and wherein each aryl or heteroaryl is optionallysubstituted with one or two substituents selected independently fromhalo, (C₁-C₆)alkyl, NR¹¹R¹², and NR¹³R¹⁴(C₁-C₆)alkyl-;

each of R⁷ and R⁸ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R⁷ and R⁸ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and

each of R⁹ and R¹⁰ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R⁹ and R¹⁰ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring;

each of R¹¹ and R¹² is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹¹ and R¹² together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and

each of R¹³ and R¹⁴ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring;

each of R¹⁵ and R¹⁶ is independently hydrogen, (C₁-C₆)alkyl, or(C₁-C₆)alkanoyl; or R¹⁵ and R¹⁶ together with the nitrogen to which theyare attached form a pyrrolidino, piperidino, piperazino, morpholino,thiomorpholino, or azepino ring;

or a salt thereof.

In one embodiment the invention also provides a compound of formula (II)or (III):

wherein:

each X is independently O, S or NH;

each R is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl orheteroaryl, wherein each (C₁-C₆)alkyl and (C₁-C₆)alkoxy is optionallysubstituted with OH, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR¹¹R¹² or—C(═O)NR¹³R¹⁴; and wherein each aryl or heteroaryl is optionallysubstituted with one or two substituents selected independently fromhalo, (C₁-C₆)alkyl, NR¹¹R¹², and NR¹³R¹⁴(C₁-C₆)alkyl-;

each of R¹¹ and R¹² is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)allylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹¹ and R¹² together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring;

each of R¹³ and R¹⁴ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and

each of R¹⁵ and R¹⁶ is independently hydrogen, (C₁-C₆)alkyl, or(C₁-C₆)alkanoyl; or R¹⁵ and R¹⁶ together with the nitrogen to which theyare attached form a pyrrolidino, piperidino, piperazino, morpholino,thiomorpholino, or azepino ring;

or a salt thereof.

The compounds of formula (I) can be prepared by forming an intermediatecomprising a linear chain of the requisite polyazoles and aminoacids, ora protective derivative thereof, then cyclizing this by forming an amidebond and optionally removing any protecting groups and/or forming asalt.

Examples of synthetic routes to compounds of formula (I) are provided inSchemes 1 to 15 below.

In cases where compounds are sufficiently basic or acidic, a salt of acompound of the invention can be useful as an intermediate for isolatingor purifying a compound of the invention. Additionally, administrationof a compound of the invention as a pharmaceutically acceptable acid orbase salt may be appropriate. Examples of pharmaceutically acceptablesalts are organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The compounds of the invention can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), a vegetable oil, a nontoxicglyceryl ester, and suitable mixtures thereof. The proper fluidity canbe maintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, e.g., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of formula (I) to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula (I) can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of formula (I) in aliquid composition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compound is conveniently administered in unit dosage form; forexample, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Compounds of the invention can also be administered in combination withother therapeutic agents, for example, other agents that are useful forthe treatment of cancer. Accordingly, in one embodiment the inventionalso provides a composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, at least one other therapeuticagent, and a pharmaceutically acceptable diluent or carrier. Theinvention also provides a kit comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, at least one other therapeuticagent, packaging material, and instructions for administering thecompound of the invention or the pharmaceutically acceptable saltthereof and the other therapeutic agent or agents to an animal to treatcancer.

The ability of a compound of the invention to stabilize G-quadroplex DNAmay be determined using pharmacological models which are well known tothe art, or using Test A described below.

Test A. Stabilization of G-Quadruplex DNA

Analyses can be performed to determine the ability of the agents to bindand thermally stabilize the duplex, triplex, and quadruplex forms ofnucleic acids. Toward this end, the UV absorbances of the nucleic acidsas a function of temperature in the absence and presence of HXDV ismonitored. The melting of duplex and triplex nucleic acids is generallyassociated with a hyperchromic shift at 260 nm while the melting ofquadruplex nucleic acids is associated with a hypochromic shift at 295nm. Thus, the temperature-dependent absorbances of duplexes andtriplexes is monitored at 260 nm, with corresponding quadruplexabsorbances being monitored at 295 nm. ST DNA, p(rA).p(rU), p(rA).p(dT),p(dA).2p(dT), p(rA).2p(rU), d(T₂AG₃)₄, and r(UG₄U) is used asrepresentative models of a DNA duplex, an RNA duplex, a hybrid DNA.RNAduplex, a DNA triplex, an RNA triplex, a DNA quadruplex, and an RNAquadruplex, respectively. All the UV melting studies are conducted at pH7.5 in the presence of potassium ions.

The ability of compounds to stabilize G-quadroplex DNA may also bedetermined using Test B described below.

Test B. Temperature-Dependent Spectrophotometry

Temperature-dependent absorption experiments are conducted on an AVIVModel 14DS Spectrophotometer (Aviv Biomedical, Lakewood, N.J.) equippedwith a thermoelectrically controlled cell holder. Quartz cells with apathlength of 1.0 cm are sed for all the absorbance studies.Temperature-dependent absorption profiles are acquired at either 260(for duplex and triplex) or 295 (for quadruplex) nm with a 5 secaveraging time. The temperature is raised in 0.5° C. increments, and thesamples are allowed to equilibrate for 1.5 min at each temperaturesetting. In the quadruplex melting studies, the concentrations ofd(T₂AG₃)₄, 9AP, 15AP, and 21AP are 5 μM in strand (120 μM innucleotide), while the concentration of r(UG₄U) is 20 μM in strand (120μM in nucleotide). In the duplex and triplex melting studies, thenucleic acid concentration is 15 μM in base pair (30 μM in nucleotide)or 15 μM in base triple (45 μM in nucleotide) and the HXDVconcentration, when present, is 15 μM. The buffer for all the UV meltingexperiments contains 10 mM EPPS (pH 7.5). In addition, sufficient KCl isadded to each solution to bring the total K⁺ concentration to either 150mM for d(T₂AG₃)₄ and p(rA).p(dT), 2 mM for r(UG₄U), 50 mM for ST DNA,250 mM for p(dA).2p(dT), or 20 mM for p(rA).2p(rU). Prior to their usein UV melting experiments, all nucleic acid solutions are preheated at90° C. for 5 min and slowly cooled to room temperature over a period of4 hr.

The anti-proliferative activity of a compound of the invention may bedetermined using pharmacological models which are well known to the art,or using Test C described below.

Test C. Evaluation of G-Quadruplex Stabilizers Using the MTT Assay.

Cell lines are selected based upon one or more factors including data ontheir relative telomerase activity, varied organ sites, availablecomparative data, and their ability to form solid tumors in athymic nudemice. The advantage of an MTT assay is that the cytotoxic/cytostaticactivities can be readily determined. Cells are cultured for 4 days at37° C. followed by addition of MTT(3-[4,5-dimethylthiozol-2-yl]-2,5-diphenyltetrazolium bromide (Sigma)(0.1 mg/ml). Cells are treated with MTT for 3 hrs and then dissolved in100 μl 100% DMSO. Absorbance is measured at OD₅₇₀ using a microplatereader (Model 3550 UV from BIO-RAD). The MTT value is normalized toOD₅₇₀ of cells treated with Cellfectin alone. Stock solutions of eachcompound are prepared. MTT assays are performed using spectrometricanalysis and 96 well plates.

The invention will now be illustrated by the following non-limitingExamples.

Example 1 Preparation of Representative Compounds of the Invention

Using procedures similar to those described herein, the followingrepresentative compounds of the invention can be prepared.

Example 2 Preparation of Representative Compounds of the Invention

Using procedures similar to those described herein, the followingrepresentative compounds of the invention can be prepared.

Example 3

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet Compound X = 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule Compound X =10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/mlCompound X = (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxidesolution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1mL (v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 01N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula (I):

wherein: the bond represented by

is a single or double bond; A is (—C(═O)NH—CH(R)—)_(x) or(—CH(R)—NH—C(═O)—)_(x); B is a group of formula:

C is (—C(═O)NH—CH(R)—)_(y or) (—CH(R)—NH—C(═O)—)_(y); n is 0, 1 or 2; pis 0, 1, or 2; x is 1 or 2; y is 0, 1 or 2; provided that the sum of n,p, x and y is 4; X is O, S or NH; one of W and Z is O, S or NH and theother of W and Z is CR⁶; each of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl or heteroaryl,wherein each (C₁-C₆)alkyl and (C₁-C₆)alkoxy is optionally substitutedwith OH, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR⁷R⁸, or —C(═O)NR⁹R¹⁰;and wherein each aryl or heteroaryl is optionally substituted with oneor two substituents selected independently from a halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, NR⁷R⁸, and NR⁷R⁸(C₁-C₆)alkyl-; each R is independentlyhydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₁-C₆)alkoxyis optionally substituted with OH, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,aryl, NR¹¹R¹², or —C(═O)NR¹³R¹⁴; and wherein each aryl or heteroaryl isoptionally substituted with one or two substituents selectedindependently from halo, (C₁-C₆)alkyl, NR¹¹R¹², andNR¹³R¹⁴(C₁-C₆)alkyl-; each of R⁷ and R⁸ is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, arylcarbonyl, heteroarylcarbonyl,(C₁-C₆)alkoxycarbonyl, carbamoyl, N—(C₁-C₆)alkylaminocarbonyl, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or(C₁-C₆)alkoxycarbony is optionally substituted with one or more NR¹⁵R¹⁶;or R⁷ and R⁸ together with the nitrogen to which they are attached forma pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, orazepino ring; and each of R⁹ and R¹⁰ is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R⁹ and R¹⁰ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; each of R¹¹ andR¹² is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, carbamoyl, N—(C₁-C₆)alkylaminocarbonyl, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or(C₁-C₆)alkoxycarbony is optionally substituted with one or more NR¹⁵R¹⁶;or R¹¹ and R¹² together with the nitrogen to which they are attachedform a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino,or azepino ring; and each of R¹³ and R¹⁴ is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹³ and R¹⁴ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; each of R¹⁵ andR¹⁶ is independently hydrogen, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; or R¹⁵and R¹⁶ together with the nitrogen to which they are attached form apyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, orazepino ring; or a salt thereof; provided that the compound of formula(I) is not YM-216391.
 2. The compound of formula (I) as claimed in claim1, wherein: the bond represented by

is a single or double bond; A is (—C(═O)NH—CH(R)—)_(x) or(—CH(R)—NH—C(═O)—)_(x); B is a group of formula:

C is (—C(═O)NH—CH(R)—)_(y or) (—CH(R)—NH—C(═O)—)_(y); n is 0, 1 or 2; pis 0, 1, or 2; x is 1 or 2; y is 0, 1 or 2; provided that the sum of n,p, x and y is 4; X is O, S or NH; one of W and Z is O, S or NH and theother of W and Z is CR⁶; each of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl or heteroaryl,wherein each (C₁-C₆)alkyl and (C₁-C₆)alkoxy is optionally substitutedwith OH, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR⁷R⁸, or —C(═O)NR⁹R¹⁰;and wherein each aryl or heteroaryl is optionally substituted with oneor two substituents selected independently from a halo, (C₁-C₆)alkyl,NR⁷R⁸, and NR⁷R⁸(C₁-C₆)alkyl-; each R is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl or heteroaryl, wherein each(C₁-C₆)alkyl and (C₁-C₆)alkoxy is optionally substituted with OH,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR¹¹R¹², or —C(═O)NR¹³R¹⁴; andwherein each aryl or heteroaryl is optionally substituted with one ortwo substituents selected independently from halo, (C₁-C₆)alkyl,NR¹¹R¹², and NR¹³R¹⁴(C₁-C₆)alkyl-; each of R⁷ and R⁸ is independentlyhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,carbamoyl, N—(C₁-C₆)alkylaminocarbonyl aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R⁷ and R⁸ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and each of R⁹and R¹⁰ is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, carbamoyl, N—(C₁-C₆)alkylaminocarbonyl, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or(C₁-C₆)alkoxycarbony is optionally substituted with one or more NR¹⁵R¹⁶;or R⁹ and R¹⁰ together with the nitrogen to which they are attached forma pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, orazepino ring; each of R¹¹ and R¹² is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹¹ and R¹² together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and each of R¹³and R¹⁴ is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, carbamoyl, N—(C₁-C₆)alkylaminocarbonyl, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or(C₁-C₆)alkoxycarbony is optionally substituted with one or more NR¹⁵R¹⁶;or R¹³ and R¹⁴ together with the nitrogen to which they are attachedform a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino,or azepino ring; each of R¹⁵ and R¹⁶ is independently hydrogen,(C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; or R¹⁵ and R¹⁶ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; or a saltthereof; provided that the compound of formula (I) is not YM-216391. 3.The compound as claimed in claim 1, in which the bond represented by

is a double bond.
 4. The compound as claimed in claim 1, which is of theformula (I′)


5. The compound as claimed in claim 1, in which each X is O.
 6. Thecompound as claimed in claim 1, in which each R is selectedindependently from hydrogen, methyl, isopropyl, 1-methylpropyl,2-methylpropyl and benzyl.
 7. A compound as claimed in claim 1 in whicheach R is selected independently from (C₁-C₆)alkyl or (C₂-C₆)alkenylwherein each (C₁-C₆)alkyl and (C₂-C₆)alkenyl, is optionally substitutedwith NR¹¹R¹².
 8. A compound as claimed in claim 1 in which each R isselected independently from aminomethyl, 2-aminoethyl, 3-aminopropyl or4-aminobutyl. 9-14. (canceled)
 15. The compound as claimed in claim 1,in which A is —C(═O)NH—CH(R)—.
 16. The compound as claimed in claim 1,in which A is —C(═O)NH—CH(R)—C(═O)NH—CH(R)—.
 17. The compound as claimedin claim 1, in which A is —C(═O)NH—CH₂—.
 18. The compound as claimed inclaim 1, in which A is —C(═O)NH—CH₂—C(═O)NH—CH₂—.
 19. The compound asclaimed in claim 1, in which A is —CH(R)—NH—C(═O)—.
 20. The compound asclaimed in claim 1, in which A is —CH(R)—NH—C(═O)—CH(R)—NH—C(═O)—. 21.The compound as claimed in claim 1, in which A is —CH₂—NH—C(═O)—. 22.The compound as claimed in claim 1, in which A is—CH₂NH—C(═O)—CH₂—NH—C(═O)—.
 23. The compound as claimed in claim 1,which is of the formula:


24. The compound as claimed in claim 1, which is of the formula:


25. The compound as claimed in claim 1, which is of the formula:


26. The compound as claimed in claim 1, which is of the formula:


27. The compound as claimed in claim 1, which is of the formula:


28. The compound as claimed in claim 1, which is of the formula:


29. The compound as claimed in claim 1, which is of the formula:


30. The compound of claim 24 wherein W is O or S and Z is CR⁶.
 31. Thecompound of claim 24 wherein Z is O or S and W is CR⁶.
 32. The compoundof claim 1 wherein the compound of formula (I) is not a compound of thefollowing formula:


33. The compound of claim 1 wherein the compound of formula (I) is not acompound of the following formula:


34. A compound of formula (II) or (III):

wherein: each X is independently O, S or NH; each R is independentlyhydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₁-C₆)alkoxyis optionally substituted with OH, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio,aryl, NR¹¹R¹², or —C(═O)NR¹³R¹⁴; and wherein each aryl or heteroaryl isoptionally substituted with one or two substituents selectedindependently from halo, (C₁-C₆)alkyl, NR¹¹R¹², andNR¹³R¹⁴(C₁-C₆)alkyl-; each of R¹¹ and R¹² is independently hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,N—(C₁-C₆)alkylaminocarbonyl, aryl or heteroaryl, wherein each(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or (C₁-C₆)alkoxycarbony is optionallysubstituted with one or more NR¹⁵R¹⁶; or R¹¹ and R¹² together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; and each of R¹³and R¹⁴ is independently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, carbamoyl, N—(C₁-C₆)alkylaminocarbonyl, aryl orheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, or(C₁-C₆)alkoxycarbony is optionally substituted with one or more NR¹⁵R¹⁶;or R¹³ and R¹⁴ together with the nitrogen to which they are attachedform a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino,or azepino ring; each of R¹⁵ and R¹⁶ is independently hydrogen,(C₁-C₆)alkyl or (C₁-C₆)alkanoyl; or R¹⁵ and R¹⁶ together with thenitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, morpholino, thiomorpholino, or azepino ring; or a saltthereof.
 35. The compound of claim 34 wherein each R is independentlyhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl or heteroaryl, wherein each(C₁-C₆)alkyl and (C₁-C₆)alkoxy is optionally substituted with OH,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryl, NR¹¹R¹², or —C(═O)NR¹³R¹⁴; andwherein each aryl or heteroaryl is optionally substituted with one ortwo substituents selected independently from halo, (C₁-C₆)alkyl,NR¹¹R¹², and NR¹³R¹⁴(C₁-C₆)alkyl-.
 36. The compound of claim 34 whereineach X is O.
 37. The compound of claim 34 wherein each R is H.
 38. Thecompound of claim 1 which is,

or a salt thereof.
 39. The compound of claim 1 which is,

or a salt thereof.
 40. A pharmaceutical composition comprising acompound of formula (I) as defined in claim 1; or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable carrier. 41.A therapeutic method for treating cancer comprising administering to amammal in need of such therapy, an effective amount of a compound offormula (I) as defined in claim 1, or a pharmaceutically acceptable saltthereof.
 42. A method to stabilize G-quadruplex DNA comprisingcontacting the G-quadruplex DNA with a compound of formula (I) asdefined in claim 1, or a salt thereof. 43-47. (canceled)